PNNL

Abstract

Chronic inhalation studies with 2-butoxyethanol conducted by National Toxicology Program identified the forestomach and liver of B6C3F1 mice as target organs for tumorigenicity. Previous studies have sown that liver tumors likely results from chronic hemolysis-induced oxidative stress. For forestomach lesions see in mice, chronic contact irritation (cytotoxicity) and regenerative hyperplasia are hypothesized to result in forestomach tumor development. To test this, experiments were conducted to address the sensitivity of mouse forestomach to BE administered by various routes. Oral administration of undiluted BE was shown to cause irritation and a compensatory proliferative response in mouse forestomach confirming that direct contact between forestomach and BE can cause irritation. However, only small amounts of BE were detected on fur of mice at the end of 6-h, whole-body or nose-only inhalation exposures to highest concentration used in the NTP chromic inhalation studies. Furthermore, no significant differences were detected in end-exposure blood concentrations of BE and butoxyacetic acid between these types of exposures. In addition, parenteral administration of BE also resulted in forestomach lesions, indicating there may be sources other than grooming for BE- or BAA-induced forestomach irritation. In pharmacokinetic study, BE and to a lesser extend BAA were eliminated more slowly from the forestomach tissue of mice than from blood or other tissues, following either oral gavage or ip injection. The forestomach was the only tissue with detectable levels of BE at 24 h. BE and BAA were both excreted in the saliva and were present in stomach contents for a prolong period of time following these routes of exposure which may further contribute to forestomach tissue dosimetry. Thus, there appear to be multiple mechanisms behind the increased levels of BE and BAA in the forestomach tissue of mice, which together can contribute to a prolong contact irritation, compensatory hyperplasia, and tumorigenicity in mice. The relevant of these effects in humans, who lack a forestomach, is questions.